Published online Sep 15, 2020. doi: 10.4239/wjd.v11.i9.374
Peer-review started: April 17, 2020
First decision: April 22, 2020
Revised: April 24, 2020
Accepted: August 4, 2020
Article in press: August 4, 2020
Published online: September 15, 2020
Processing time: 147 Days and 3.9 Hours
As a class of promising anti-diabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to prevent β cells from apoptosis and potentiate insulin secretion in a glucose-dependent manner, which can decrease blood glucose levels without the risk of hypoglycemia. Long noncoding RNAs (lncRNA) are transcripts that are longer than 200 nucleotides and do not code for proteins. Growing evidence demonstrates that lncRNAs regulate mRNA expression by competing with miRNAs, which was termed as “ceRNA mechanism”. Studies have demonstrated that ceRNA mechanism is widely involved in multiple biological processes, including insulin signal transduction that may affect diabetes development. Currently, the mechanisms of the protective effect of GLP-1RA on β cells have been widely investigated; however, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated.
Is there any specific lncRNAs that participate in the protective effect of GLP-1RAs in β cells? What is the mechanism of lncRNAs involved in this process? Answering these questions will provide significant insight in understanding the mechanisms of GLP-1RA function at the transcription level.
We and other researchers found that geniposide potentiates insulin secretion, promotes proliferation, and decreases the rate of β cell apoptosis by stimulating the GLP-1 receptor. In this study, we further identified the lncRNAs and mRNAs that were involved in the protective effect of geniposide on β cells, and their roles. This will be helpful for in-depth exploration of the mechanism of GLP-1RAs function in β cells.
Rat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in β cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous (ceRNA) mechanism was explored through miRanda and TargetScan databases.
We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc, Htr2a, and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc.) co-expressed with the three hub mRNAs (Pomc, Htr2a, and Agtr1a) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs (rno-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc.) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network.
We have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in β cells.
The “ceRNA mechanism”, which is widely involved in multiple biological processes, mediates the protective effect of GLP-1RAs in β cells. The value of bioinformatics allows scientists to create comprehensive databases of biological and health information that can be used to test theories and generate solutions to medical problems that affect us all.